The present invention, in some embodiments thereof, relates to pharmaceutical compositions and methods of use thereof for treating hypoxia-related diseases and, more particularly, to pharmaceutical compositions including TPEN and an alginate compound as active ingredients.
Hypoxic-Ischemic injury results from a tissue restriction in blood supply leading to a mismatch between oxygen supply and demand, which may result in cell necrosis. Restoration of oxygenated blood to an ischemic tissue, i.e., reoxygenation, may give rise to a more severe tissue damage which is usually associated with programmed cell death, namely apoptosis. The link between these two events is known as ischemia-reperfusion injury (IRI). Hence minimizing IRI has broad range clinical implications. IRI is regarded as a redox active metal and free radical mediated cascade that occurs during acute myocardial infarction, stroke, thrombolysis, and other pathological situations associated with ischemia followed by reoxygenation/reperfusion. This type of injury/damage to tissue and organs also occurs in the post-ischemic reperfusion during medical procedures such as cardiopulmonary bypass, percutaneous coronary intervention, coronary angioplasty and other thrombolytic procedures.
Biologically important transition-metals, such as copper, iron and zinc, are also redox active metals and have been found to play a critical mediatory role in reperfusion-induced myocardial damage. Hence, their intracellular transport is tightly regulated and under normal physiological conditions, are stored in situ within protective intracellular stores proteins like ferritin and ceruloplasmin.
However, under situations as hypoxia-ischemia they are frequently released from their stores and subjected to high oxygen level upon initiating reperfusion. The result is the triggering of redox-active catalysis processes and formation of harmful free radicals, so called reactive oxygen species (ROS) via the Fenton and Haber-Weiss reactions.
ROS are involved in and mediates many diseases, syndromes and pathologies, such as heart and brain stroke, brain trauma, organs transplants rejection, various neurodegenerative diseases, arthritis, etc.
Ischemia-induced high accumulation of intracellular transition metals as iron, copper and also zinc which significantly contributed to organ injury like ischemic brain damage through promotion of neuronal apoptotic death. Removing zinc by chelating agents may be an effective approach to reduce ischemic brain injury.
U.S. Pat. No. 5,082,851 to the present inventor teaches a metal chelating agent, N,N,N′,N′-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN), being capable of protecting heart tissue from ischemia-reperfusion damage. This high specificity heavy metal chelating agent is thought to work by changing the redox potential of redox-active metals (transition metals), into an inactive form before the onset of reoxygenation and hence preventing the yield and the release of hazardous reactive oxygen species (ROS).
International patent application WO 2013/003445 teaches that TPEN is capable of providing heart cells up to, but not greater than, 70% protection from hypoxia stress injury. The effective concentration range of TPEN was between about 1 to about 10 μM. TPEN administered at higher concentrations resulted in decreasing protection efficacy (Journal of Muscle Research and Cell Motility, October 2007, Volume 28, issues 7-8, pp. 421-428).
There is thus a widely recognized need for, and it would be highly advantageous to have, pharmaceutical compositions for treating hypoxia-related diseases which are effective and devoid of the above limitations.